1. Field of the Invention
The present invention relates to a polymeric micelle composition, and more specifically, to a polymeric micelle composition comprising an amphiphilic block copolymer composed of a hydrophilic block and a hydrophobic block, and a polylactic acid derivative having at least one terminal carboxyl group.
2. Related Art
Recently, nanoparticle and polymeric micelle systems using biodegradable polymers have been reported to be extremely useful technologies which can alter the in vivo distribution of an intravenously administered drug thereby reducing its side effects and improving its efficacy. These systems offer advantages such as specific cell targeting and control of the release of the drug. They also have good compatibility with body fluids and improve the solubility and bioavailability of poorly water-soluble drugs.
A method for preparing block copolymer micelles by physically entrapping a drug in the block copolymer which is composed of a hydrophilic component and a hydrophobic component was disclosed in EP 0 583,955A2, and JP 206,815/94. The block copolymer employed is an A-B type diblock copolymer comprising a polyethylene oxide as the hydrophilic A component and a polyamino acid or derivatives thereof having a hydrophobic functional group as the hydrophobic B component. Polymeric micelles comprising the above block copolymer can physically incorporate a drug, e.g. adriamycin, indomethacin, etc. into the inner core of the polymeric micelles, which can then be used as a drug delivery carrier. However, these polymeric micelles are comprised of block copolymers that cannot be readily degraded in vivo. In addition, the b lock copolymers have poor biocompatibility, which can cause undesirable side effects when administered in vivo.
Great effort has been devoted to the development of a biodegradable and biocompatible core-shell type drug carrier with improved stability and efficacy, and which will entrap a poorly water-soluble drug. A method for preparation of chemically fixed polymeric micelles, wherein the polymer is a core-shell type polymer comprising a hydrophilic polyethylene oxide as the shell and a hydrophobic biodegradable polymer that is cross-linked in an aqueous solution as the core, was disclosed in EP 0,552,802A2. However, this polymeric micelle is difficult to prepare because crosslinkers must be introduced into the hydrophobic component of the A-B type diblock or A-B-A type triblock copolymer so that the core-forming polymer has a stable structure. Also, administering a crosslinker that has never been used in the human body leads to safety concerns.
On the other hand, in order to solubilize a hydrophobic drug, there has been reported a polymeric micelle composed of a di- or tri-block copolymer comprising a hydrophilic polymer of polyalkylene glycol derivatives and a hydrophobic biodegradable polymer such as fatty acid polyesters or polyamino acids. U.S. Pat. No. 5,449,513 discloses a diblock copolymer comprising polyethylene glycol as the hydrophilic polymer, and a polyamino acid derivative, e.g. polybenzyl aspartic acid, etc. as the hydrophobic polymer. This diblock copolymer can solubilize hydrophobic anticancer agents, e.g. doxorubicin, or anti-inflammatory agents, e.g. indomethacin. However, the polyamino acid derivatives cannot be hydrolyzed in vivo, and thus cause side effects due to immune responses.
U.S. Pat. No. 5,429,826 discloses a di- or multi-block copolymer comprising a hydrophilic polyalkylene glycol and a hydrophobic polylactic acid. Specifically, the above patent describes a method of stabilizing polymeric micelles by micellizing a di- or multi-block copolymer wherein an acrylic acid derivative is bonded to a terminal group of the di- or multi-block copolymer in an aqueous solution, which then crosslinks the polymers in order to form the micelles. The above method could accomplish stabilization of the polymeric micelle, but the crosslinked polymer is not degraded, and thus, cannot be applied for in vivo use. The above polymeric micelles can solubilize a large amount of a poorly water-soluble drug in an aqueous solution with a neutral pH, but have the drawback that they release the drug within a short period of time.
In view of the foregoing, development of an improved polymeric micelle composition for hydrophobic drug delivery that is biocompatible and biodegradable will be appreciated and desired. Thus, the present invention provides such an improved polymeric micelle composition which is biocompatible and biodegradable and which can effectively deliver a hydrophobic drug without a decrease in its stability.